RESUMEN
Alzheimer's disease (AD) is the main type of dementia and is a disease with a profound socioeconomic burden due to the lack of effective treatment. In addition to genetics and environmental factors, AD is highly associated with metabolic syndrome, defined as the combination of hypertension, hyperlipidemia, obesity and type 2 diabetes mellitus (T2DM). Among these risk factors, the connection between AD and T2DM has been deeply studied. It has been suggested that the mechanism linking both conditions is insulin resistance. Insulin is an important hormone that regulates not only peripheral energy homeostasis but also brain functions, such as cognition. Insulin desensitization, therefore, could impact normal brain function increasing the risk of developing neurodegenerative disorders in later life. Paradoxically, it has been demonstrated that decreased neuronal insulin signalling can also have a protective role in aging and protein-aggregation-associated diseases, as is the case in AD. This controversy is fed by studies focused on neuronal insulin signalling. However, the role of insulin action on other brain cell types, such as astrocytes, is still unexplored. Therefore, it is worthwhile exploring the involvement of the astrocytic insulin receptor in cognition, as well as in the onset and/or development of AD.
Asunto(s)
Enfermedad de Alzheimer , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Síndrome Metabólico , Humanos , Enfermedad de Alzheimer/metabolismo , Síndrome Metabólico/metabolismo , Resistencia a la Insulina/fisiología , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Encéfalo/metabolismo , Insulina Regular Humana , Factores de RiesgoRESUMEN
In this study, the plausible role of trimethylamine N-oxide (TMAO), a microbiota metabolite, was investigated as a link between peripheral inflammation and the inflammation of the central nervous system using different cell lines. TMAO treatment favored the differentiation of adipocytes from preadipocytes (3T3-L1 cell line). In macrophages (RAW 264.7 cell line), which infiltrate adipose tissue in obesity, TMAO increased the expression of pro-inflammatory cytokines. The treatment with 200 µM of TMAO seemed to disrupt the blood-brain barrier as it induced a significant decrease in the expression of occludin in hCMECs. TMAO also increased the expression of pro-inflammatory cytokines in primary neuronal cultures, induced a pro-inflammatory state in primary microglial cultures, and promoted phagocytosis. Data obtained from this project suggest that microbial dysbiosis and increased TMAO secretion could be a key link between peripheral and central inflammation. Thus, TMAO-decreasing compounds may be a promising therapeutic strategy for neurodegenerative diseases.
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Inflamación , Metilaminas , Humanos , Inflamación/metabolismo , Metilaminas/farmacología , Metilaminas/metabolismo , Citocinas , Proyectos de InvestigaciónRESUMEN
The morphological changes that occur in the central nervous system of patients with severe acute intermittent porphyria (AIP) have not yet been clearly established. The aim of this work was to analyze brain involvement in patients with severe AIP without epileptic seizures or clinical posterior reversible encephalopathy syndrome, as well as in a mouse model receiving or not liver-directed gene therapy aimed at correcting the metabolic disorder. We conducted neuroradiologic studies in 8 severely affected patients (6 women) and 16 gender- and age-matched controls. Seven patients showed significant enlargement of the cerebral ventricles and decreased brain perfusion was observed during the acute attack in two patients in whom perfusion imaging data were acquired. AIP mice exhibited reduced cerebral blood flow and developed chronic dilatation of the cerebral ventricles even in the presence of slightly increased porphyrin precursors. While repeated phenobarbital-induced attacks exacerbated ventricular dilation in AIP mice, correction of the metabolic defect using liver-directed gene therapy restored brain perfusion and afforded protection against ventricular enlargement. Histological studies revealed no signs of neuronal loss but a denser neurofilament pattern in the periventricular areas, suggesting compression probably caused by imbalance in cerebrospinal fluid dynamics. In conclusion, severely affected AIP patients exhibit cerebral ventricular enlargement. Liver-directed gene therapy protected against the morphological consequences of the disease seen in the brain of AIP mice. The observational study was registered at Clinicaltrial.gov as NCT02076763.
Asunto(s)
Encéfalo/patología , Ventrículos Cerebrales/patología , Modelos Animales de Enfermedad , Hidroximetilbilano Sintasa/genética , Porfiria Intermitente Aguda/fisiopatología , Adulto , Animales , Encéfalo/metabolismo , Estudios de Casos y Controles , Ventrículos Cerebrales/metabolismo , Ensayos Clínicos Fase I como Asunto , Femenino , Terapia Genética , Humanos , Masculino , Ratones , Persona de Mediana Edad , Porfiria Intermitente Aguda/genética , Porfiria Intermitente Aguda/metabolismo , Estudios ProspectivosRESUMEN
Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of rare lymphoid malignancies that mostly have poor prognoses with currently available treatments. Upfront consolidation with autologous stem cell transplantation (ASCT) is frequently carried out, but its efficacy has never been investigated in randomized trials. We designed a multicenter, international, retrospective study with the main objective of comparing progression-free survival and overall survival of patients with PTCL who underwent ASCT in complete remission (CR) after first-line chemotherapy with a control group who did not undergo ASCT. From the initial population of 286 registered patients, 174 patients with PTCL other than anaplastic large cell lymphoma, ALK-positive, deemed fit for ASCT at the time of diagnosis, and who were in CR or uncertain CR after induction therapy (CR1) were included in our analysis. one hundred and three patients underwent ASCT, whereas 71 did not, in most cases (n=53) because the physician decided against it. With a median follow-up of 65.5 months, progression-free survival was significantly better in the transplanted patients than in the non-transplanted group: 63% versus 48% at 5 years (P=0.042). Overall survival was significantly longer for ASCT patients in the subgroup with advanced stage at diagnosis (5-year overall survival: 70% vs. 50%, P=0.028). In the multivariate analysis, first-line ASCT was associated with significantly prolonged progression-free survival (HR=0.57, 95% CI: 0.35-0.93) and overall survival (HR=0.57, 95% CI: 0.33-0.99). In conclusion, our study supports the use of ASCT as a consolidation strategy for patients with PTCL in CR1. These results should be confirmed in a prospective randomized study.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Linfoma de Células T Periférico , Humanos , Trasplante Autólogo , Trasplante de Células Madre Hematopoyéticas/métodos , Estudios Retrospectivos , Estudios Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Supervivencia sin EnfermedadRESUMEN
Recent investigations have increased the interest on the connection between the microorganisms inhabiting the gut (gut microbiota) and human health. An imbalance of the intestinal bacteria representation (dysbiosis) could lead to different diseases, ranging from obesity and diabetes, to neurological disorders including Alzheimer's disease (AD). The term "gut-brain axis" refers to a crosstalk between the brain and the gut involving multiple overlapping pathways, including the autonomic, neuroendocrine, and immune systems as well as bacterial metabolites and neuromodulatory molecules. Through this pathway, microbiota can influence the onset and progression of neuropathologies such as AD. This review discusses the possible interaction between the gut microbiome and AD, focusing on the role of gut microbiota in neuroinflammation, cerebrovascular degeneration and Aß clearance.
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Enfermedad de Alzheimer , Microbioma Gastrointestinal , Enfermedad de Alzheimer/patología , Bacterias/metabolismo , Encéfalo/metabolismo , Disbiosis , HumanosRESUMEN
The brain is one of the most energy-consuming organs in the body. Satisfying such energy demand requires compartmentalized, cell-specific metabolic processes, known to be complementary and intimately coupled. Thus, the brain relies on thoroughly orchestrated energy-obtaining agents, processes and molecular features, such as the neurovascular unit, the astrocyte-neuron metabolic coupling, and the cellular distribution of energy substrate transporters. Importantly, early features of the aging process are determined by the progressive perturbation of certain processes responsible for adequate brain energy supply, resulting in brain hypometabolism. These age-related brain energy alterations are further worsened during the prodromal stages of neurodegenerative diseases, namely Alzheimer's disease (AD), preceding the onset of clinical symptoms, and are anatomically and functionally associated with the loss of cognitive abilities. Here, we focus on concrete neuroenergetic features such as the brain's fueling by glucose and lactate, the transporters and vascular system guaranteeing its supply, and the metabolic interactions between astrocytes and neurons, and on its neurodegenerative-related disruption. We sought to review the principles underlying the metabolic dimension of healthy and AD brains, and suggest that the integration of these concepts in the preventive, diagnostic and treatment strategies for AD is key to improving the precision of these interventions.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/metabolismo , Astrocitos/metabolismo , Encéfalo/metabolismo , Humanos , Neuronas/metabolismoRESUMEN
Obesity and aging are becoming increasingly prevalent across the globe. It has been established that aging is the major risk factor for Alzheimer's disease (AD), and it is becoming increasingly evident that obesity and the associated insulin resistance are also notably relevant risk factors. The biological plausibility of the link between high adiposity, insulin resistance, and dementia is central for understanding AD etiology, and to form bases for prevention efforts to decrease the disease burden. Several studies have demonstrated a strong association between short chain fatty acid receptor FFAR3 and insulin sensitivity. Interestingly, it has been recently established that FFAR3 mRNA levels are increased in early stages of the AD pathology, indicating that FFAR3 could play a key role in AD onset and progression. Indeed, in the present study we demonstrate that the ablation of the Ffar3 gene in Tg2576 mice prevents the development of cognitive deficiencies in advanced stages of the disease. Notably, this cognitive improvement is also maintained upon a severe metabolic challenge such as the exposure to high-fat diet (HFD) feeding. Moreover, FFAR3 deletion restores the brain hypermetabolism displayed by Tg2576 mice. Collectively, these data postulate FFAR3 as a potential novel target for AD.
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Enfermedad de Alzheimer , Resistencia a la Insulina , Animales , Ratones , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Cognición , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Resistencia a la Insulina/genética , Ratones Endogámicos C57BL , Ratones Transgénicos , Obesidad/genética , Obesidad/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
We conducted a phase 2 trial to evaluate the safety and efficacy of bendamustine instead of BCNU (carmustine) in the BEAM (BCNU, etoposide, cytarabine and melphalan) regimen (BendaEAM) as conditioning for autologous stem-cell transplantation (ASCT) in patients with aggressive lymphomas. The primary endpoint was 3-year progression-free survival (PFS). Sixty patients (median age 55 [28-71] years) were included. All patients (except one who died early) engrafted after a median of 11 (9-72) and 14 (4-53) days to achieve neutrophil and platelet counts of >0.5 × 109 /l and >20 × 109 /l, respectively. Non-relapse mortality at 100 days and 1 year were 3.3% and 6.7%, respectively. With a median follow-up of 67 (40-77) months, the estimated 3-year PFS and overall survival (OS) were 58% and 75%, respectively. Patients in partial response at study entry had significantly worse PFS and OS than patients who underwent ASCT in complete metabolic remission, and this was the only prognostic factor associated with both PFS (Relative risk [RR], 0.27 [95% confidence interval {CI} [0.12-0.56]) and OS (RR, 0.40 [95% CI 0.17-0.97]) in the multivariate analysis. BendaEAM conditioning is therefore a feasible and effective regimen in patients with aggressive lymphomas. However, patients not in complete metabolic remission at the time of transplant had poorer survival and so should be considered for alternative treatment strategies.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Clorhidrato de Bendamustina/administración & dosificación , Linfoma/mortalidad , Linfoma/terapia , Trasplante de Células Madre de Sangre Periférica , Acondicionamiento Pretrasplante , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Autoinjertos , Clorhidrato de Bendamustina/efectos adversos , Carmustina/administración & dosificación , Carmustina/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Melfalán/administración & dosificación , Melfalán/efectos adversos , Persona de Mediana Edad , Podofilotoxina/administración & dosificación , Podofilotoxina/efectos adversos , Tasa de SupervivenciaRESUMEN
Fanconi anemia (FA) is a rare genomic instability disorder characterized by progressive bone marrow failure and predisposition to cancer. FA-associated gene products are involved in the repair of DNA interstrand crosslinks (ICLs). Fifteen FA-associated genes have been identified, but the genetic basis in some individuals still remains unresolved. Here, we used whole-exome and Sanger sequencing on DNA of unclassified FA individuals and discovered biallelic germline mutations in ERCC4 (XPF), a structure-specific nuclease-encoding gene previously connected to xeroderma pigmentosum and segmental XFE progeroid syndrome. Genetic reversion and wild-type ERCC4 cDNA complemented the phenotype of the FA cell lines, providing genetic evidence that mutations in ERCC4 cause this FA subtype. Further biochemical and functional analysis demonstrated that the identified FA-causing ERCC4 mutations strongly disrupt the function of XPF in DNA ICL repair without severely compromising nucleotide excision repair. Our data show that depending on the type of ERCC4 mutation and the resulting balance between both DNA repair activities, individuals present with one of the three clinically distinct disorders, highlighting the multifunctional nature of the XPF endonuclease in genome stability and human disease.
Asunto(s)
Proteínas de Unión al ADN/genética , Desoxirribonucleasas/genética , Anemia de Fanconi/genética , Predisposición Genética a la Enfermedad/genética , Fenotipo , Apoptosis/genética , Apoptosis/efectos de la radiación , Secuencia de Bases , Exoma/genética , Anemia de Fanconi/patología , Mutación de Línea Germinal/genética , Humanos , Immunoblotting , Inmunoprecipitación , Datos de Secuencia Molecular , Análisis de Secuencia de ADN , Rayos UltravioletaRESUMEN
Elements of the endocannabinoid system are strongly expressed in the basal ganglia where they suffer profound rearrangements after dopamine depletion. Modulation of the levels of the endocannabinoid 2-arachidonoyl-glycerol by inhibiting monoacylglycerol lipase alters glial phenotypes and provides neuroprotection in a mouse model of Parkinson's disease. In this study, we assessed whether inhibiting fatty acid amide hydrolase could also provide beneficial effects on the time course of this disease. The fatty acid amide hydrolase inhibitor, URB597, was administered chronically to mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp) over 5weeks. URB597 (1mg/kg) prevented MPTPp induced motor impairment but it did not preserve the dopamine levels in the nigrostriatal pathway or regulate glial cell activation. The symptomatic relief of URB597 was confirmed in haloperidol-induced catalepsy assays, where its anti-cataleptic effects were both blocked by antagonists of the two cannabinoid receptors (CB1 and CB2), and abolished in animals deficient in these receptors. Other fatty acid amide hydrolase inhibitors, JNJ1661010 and TCF2, also had anti-cataleptic properties. Together, these results demonstrate an effect of fatty acid amide hydrolase inhibition on the motor symptoms of Parkinson's disease in two distinct experimental models that is mediated by cannabinoid receptors.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Ácidos Araquidónicos/metabolismo , Benzamidas/farmacología , Agonistas de Receptores de Cannabinoides/metabolismo , Carbamatos/farmacología , Endocannabinoides/metabolismo , Trastornos Parkinsonianos/tratamiento farmacológico , Alcamidas Poliinsaturadas/metabolismo , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB2/antagonistas & inhibidores , Animales , Benzamidas/administración & dosificación , Carbamatos/administración & dosificación , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Diabetic nephropathy (DN) is a major complication of diabetic patients and the leading cause of end-stage renal disease. Glomerular dysfunction plays a critical role in DN, but deterioration of renal function also correlates with tubular alterations. Human DN is characterized by glycogen accumulation in tubules. Although this pathological feature has long been recognized, little information exists about the triggering mechanism. In this study, we detected over-expression of muscle glycogen synthase (MGS) in diabetic human kidney. This enhanced expression suggests the participation of MGS in renal metabolic changes associated with diabetes. HK2 human renal cell line exhibited an intrinsic ability to synthesize glycogen, which was enhanced after over-expression of protein targeting to glycogen. A correlation between increased glycogen amount and cell death was observed. Based on a previous transcriptome study on human diabetic kidney disease, significant differences in the expression of genes involved in glycogen metabolism were analyzed. We propose that glucose, but not insulin, is the main modulator of MGS activity in HK2 cells, suggesting that blood glucose control is the best approach to modulate renal glycogen-induced damage during long-term diabetes.
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Diabetes Mellitus Tipo 2/enzimología , Nefropatías Diabéticas/enzimología , Regulación Enzimológica de la Expresión Génica , Glucógeno Sintasa/biosíntesis , Músculos/enzimología , Anciano , Células Cultivadas , Diabetes Mellitus Tipo 2/patología , Nefropatías Diabéticas/patología , Femenino , Perfilación de la Expresión Génica , Glucógeno Sintasa/metabolismo , Humanos , Inmunohistoquímica , Masculino , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
BACKGROUND: Obesity has been associated with various health disorders, including psychological alterations. Cocoa consumption and weight management may produce a beneficial effect on these problems. OBJECTIVE: The purpose of this study was to investigate the effect of cocoa extract supplementation as part of an energy-restricted diet on psychological status and peripheral dopaminergic activity in overweight or obese middle-aged subjects. METHODS: In a 4-wk, double-blind, randomized, placebo-controlled parallel nutritional intervention, 22 men and 25 women [mean ± SD age: 57 ± 5 y; body mass index (kg/m2): 30.6 ± 2.3] were studied. After a 1-wk run-in period, volunteers consumed 15% energy-restricted diets; one-half of the volunteers were randomly assigned to receive ready-to-eat meals supplemented with 1.4 g cocoa extract/d (645 mg total polyphenols/d), whereas the rest of the volunteers received the same meals without cocoa supplementation. Plasma monoamines [dopamine, dopac, and homovanillic acid (HVA)], monoamine oxidase (MAO), and psychological status (anxiety and depressive symptoms) were analyzed in fasting participants at baseline and endpoint. Data were analyzed over time, and regression and correlation analyses were conducted to determine the relation between variables. RESULTS: Depressive symptoms decreased in both groups after the intervention (control: -9.4%, P < 0.001; cocoa: -6.3%, P = 0.008), but anxiety symptoms did not. The increase in plasma HVA was 11.5% greater in the cocoa group than in the control group (P = 0.016), but plasma dopamine, dopac, and MAO changes did not differ between groups. A negative relation between changes in depressive symptoms and changes in plasma HVA was observed in the cocoa group (ß = -0.39, P = 0.029). Moreover, the change in plasma dopamine was positively associated with the change in methyl-catechin-O-glucoronide in the cocoa-supplemented group (r = 0.69, P = 0.019). CONCLUSION: The intake of cocoa extract by participants consuming a 15% energy-restricted diet contributed to an increase in plasma HVA concentrations. This change was associated with a reduction in depressive symptoms, suggesting a potential effect of cocoa extract intake on this relation. The present results are secondary analyses of a clinical trial that was registered at www.clinicaltrials.gov as NCT01596309.
RESUMEN
Education and cognitive occupations are commonly associated to reduce risk of Alzheimer's disease (AD) or dementia. Animal studies have demonstrated that cognitive stimulation (CS) achieved by social/physical activities and/or enriched environments compensates for memory decline. We have elaborated a novel paradigm of CS that is devoid of physical/social activity and enriched environments. 4 month-old Tg2576 mice were cognitively trained for 8 weeks and, after a break of 8 months, long-lasting effects of CS on cognitive abilities and AD-like pathology were measured. Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests showed that deficits in spatial and recognition memories were compensated by CS. These outcomes were accompanied by increased levels of hippocampal post-synaptic markers (PSD95 and NR1) and proteins involved in synaptic formation (Arc, ß-catenin). CS softened amyloid pathology in terms of reduced levels of Aß1-42 and the dodecameric assembly, referred as Aß*56. CS appeared to affect the APP processing since differences in levels of ADAM17, BACE1 and C99/C83 ratio were found. Tau hyper-phosphorylation and high activities of tau kinases were also reduced by CS. In contrast, CS did not induce any of these molecular changes in wild-type mice. The present findings suggest beneficial and long-lasting effects of CS early in life on cognitive decline and AD-like pathology.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Precursor de Proteína beta-Amiloide/biosíntesis , Conducta Animal , Cognición , Aprendizaje por Laberinto , Antígeno 12E7 , Proteínas ADAM/biosíntesis , Proteínas ADAM/genética , Proteína ADAM17 , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Secretasas de la Proteína Precursora del Amiloide/biosíntesis , Secretasas de la Proteína Precursora del Amiloide/genética , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Antígenos CD/biosíntesis , Antígenos CD/genética , Ácido Aspártico Endopeptidasas/biosíntesis , Ácido Aspártico Endopeptidasas/genética , Biomarcadores/metabolismo , Proteínas Portadoras/biosíntesis , Proteínas Portadoras/genética , Modelos Animales de Enfermedad , Homólogo 4 de la Proteína Discs Large , Femenino , Guanilato-Quinasas/biosíntesis , Guanilato-Quinasas/genética , Hipocampo/metabolismo , Hipocampo/patología , Hipocampo/fisiopatología , Humanos , Inmunoglobulinas/biosíntesis , Inmunoglobulinas/genética , Glicoproteínas de Membrana/biosíntesis , Glicoproteínas de Membrana/genética , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Receptores de N-Metil-D-Aspartato , Antígeno CD83RESUMEN
It is becoming evident that chronic exposure to stress not only might result in insulin resistance or cognitive deficits, but may also be considered a risk factor for pathologies such as depression or Alzheimer's disease (AD). There is great interest in determining the molecular mechanisms underlying interactions between stress, aging, memory and Alzheimer's disease (AD). We have used the chronic mild stress (CMS) model to study the effects of chronic stress on the aging process and the development of central insulin resistance and AD pathology. CMS aged mice showed cognitive impairments in the novel object recognition test. In addition, CMS aged mice displayed both peripheral insulin resistance, as shown by HOMA index, and decreased hippocampal levels of pIRS and downstream intracellular signaling (pAKT, pGSK and pERK1/2). Interestingly, there was a significant increase in both C99:C83 ratio and BACE1 levels in the hippocampus of CMS aged mice. Increased expression of the AD marker pTau was also found in stressed aged mice. Increased expression of the stress-activated protein kinase JNK was found in CMS aged mice, accompanied by significant decreases in glucocorticoid receptor (GR) expression and increases in mineralocorticoid receptor (MR) expression. It is suggested that the interaction of stress with aging should be considered when studying determinants of the onset and progression of AD.
Asunto(s)
Envejecimiento/patología , Enfermedad de Alzheimer/etiología , Trastornos del Conocimiento/etiología , Resistencia a la Insulina , Trastornos de la Memoria/etiología , Estrés Psicológico/complicaciones , Envejecimiento/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales , Western Blotting , Enfermedad Crónica , Trastornos del Conocimiento/patología , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/patología , Insulina/sangre , Trastornos de la Memoria/patología , Ratones , Ratones Endogámicos C57BL , Fosforilación , Estrés Psicológico/patologíaRESUMEN
The use of highly effective rituximab-containing therapy for treating diffuse large B-cell lymphoma (DLBCL) makes it more difficult to salvage relapsed or refractory patients. Autologous stem-cell transplantation (ASCT) is the reference treatment for these patients, but the impact of previous exposure to rituximab on the subsequent results of ASCT remains unknown. We analysed 248 patients with relapsed or refractory DLBCL or grade 3B follicular lymphoma pre-treated with rituximab as part of first-line therapy (R+ group) who received ASCT, in comparison with a control group of 127 patients without previous exposure to rituximab (R- group). The complete remission (CR) rates were similar in both groups. Multivariate analysis identified age-adjusted International Prognostic Index at diagnosis, extranodal involvement and disease status at transplant, and the number of previous chemotherapy lines as independent factors with a negative influence on CR rate. Compared with R- patients, those in the R+ group had a significantly better progression-free survival (63% vs. 48% at 5 years) and overall survival (72% vs. 61% at 5 years). This observation was independent of other prognostic factors that affected these outcomes. In conclusion, ASCT is no less effective in patients with relapsed or refractory aggressive B-cell lymphoma pre-treated with first-line rituximab-containing therapy than in rituximab-naive patients.
Asunto(s)
Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Trasplante de Médula Ósea , Linfoma de Células B Grandes Difuso/terapia , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Femenino , Supervivencia de Injerto/efectos de los fármacos , Humanos , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pronóstico , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Rituximab , Terapia Recuperativa/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
Chronic exposure to glucocorticoids might result not only in insulin resistance or cognitive deficits, but it is also considered as a risk factor for pathologies such as Alzheimer's disease. Propranolol is a ß-adrenergic antagonist commonly used in the treatment of hypertension or acute anxiety. The effects of propranolol (5 mg/kg) have been tested in a model of chronic corticosterone administration (100 µg/ml, 4 wk) in drinking water. Corticosterone administration led to cognitive impairment in the novel object recognition test that was reversed by propranolol. Increased levels of Aß in the hippocampus of corticosterone-treated mice were counteracted by propranolol treatment, purportedly through an increased IDE expression. Chronic corticosterone treatment induced responses characteristic of insulin resistance, as increased peripheral insulin levels, decreased activation of the insulin receptor (pIR) and decreased associated intracellular pathways (pAkt). These effects might be related to a decreased c-Jun N terminal kinase 1 expression. Again, propranolol was able to counteract all corticosterone-induced effects. One of the main kinases involved in tau phosphorylation, glycogen synthase kinase 3ß (GSK3ß), which is inactivated by phosphorylation by pAkt, was found to be decreased after corticosterone and increased after propranolol treatment. Concomitant changes in pTau expression were found. Overall, these data further strengthen the potential of propranolol as a therapeutic agent for pathologies associated with the interaction glucocorticoids-insulin resistance and the development of relevant cellular processes for Alzheimer's disease.
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Antagonistas Adrenérgicos beta/uso terapéutico , Péptidos beta-Amiloides/metabolismo , Trastornos del Conocimiento/tratamiento farmacológico , Corticosterona/toxicidad , Resistencia a la Insulina/fisiología , Propranolol/uso terapéutico , Proteínas tau/metabolismo , Animales , Trastornos del Conocimiento/inducido químicamente , Modelos Animales de Enfermedad , Insulina/sangre , Masculino , Ratones , Ratones Endogámicos AKR , Actividad Motora/efectos de los fármacos , Fosforilación/efectos de los fármacos , Reconocimiento en Psicología/efectos de los fármacosRESUMEN
The efficacy of antihypertensive agents in Alzheimer's disease (AD) is controversial. It has been tested here whether some antihypertensive drugs might influence AD through mechanisms independent of blood pressure-lowering activity. The effects of treatment with the antihypertensive propranolol on cognition and AD-related markers have been studied in the Tg2576 mouse model of AD. Propranolol, at a lower dose than that used as antihypertensive (5 mg/kg, 6 wk), attenuated cognitive impairments shown by Tg2576 mice aged 9 months in the novel object recognition and fear conditioning tests. Propranolol was also able to counteract the increases in hippocampal levels of Aß(42) present in Tg2576 mice. This effect was accompanied by an increased expression of insulin degrading enzyme. Changes in markers of synaptic pathology, as shown by decreases in phosphorylation of Akt and in the expression of BDNF in Tg2676 mice, were also counteracted by propranolol treatment. Tau hyperphosphorylation shown by Tg2576 mice was also decreased in the hippocampus of propranolol-treated mice, an effect probably related to an increase of GSK3ß phosphorylation (inactive form) and a decreased JNK1 expression. Overall, these data further strengthen the potential of propranolol as a therapeutic agent for AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Precursor de Proteína beta-Amiloide/metabolismo , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Trastornos del Conocimiento/tratamiento farmacológico , Cognición/efectos de los fármacos , Propranolol/farmacología , Proteínas tau/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Células Cultivadas , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/patología , Trastornos del Conocimiento/psicología , Modelos Animales de Enfermedad , Miedo/efectos de los fármacos , Femenino , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Actividad Motora/efectos de los fármacos , Mutación , Plasticidad Neuronal/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Reconocimiento en Psicología/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Nowadays, oxidative cell damage is one of the common features of cancer and Alzheimer's disease (AD), and Se-containing molecules, such as ebselen, which has demonstrated strong antioxidant activity, have demonstrated well-established preventive effects against both diseases. In this study, a total of 39 Se-derivatives were synthesized, purified, and spectroscopically characterized by NMR. Antioxidant ability was tested using the DPPH assay, while antiproliferative activity was screened in breast, lung, prostate, and colorectal cancer cell lines. In addition, as a first approach to evaluate their potential anti-Alzheimer activity, the in vitro acetylcholinesterase inhibition (AChEI) was tested. Regarding antioxidant properties, compound 13a showed concentration- and time-dependent radical scavenging activity. Additionally, compounds 14a and 17a showed high activity in the melanoma and ovarian cancer cell lines, with LD50 values below 9.2 µM. Interestingly, in the AChEI test, compound 14a showed almost identical inhibitory activity to galantamine along with a 3-fold higher in vitro BBB permeation (Pe = 36.92 × 10-6 cm/s). Molecular dynamics simulations of the aspirin derivatives (14a and 14b) confirm the importance of the allylic group instead of the propargyl one. Altogether, it is concluded that some of these newly synthesized Se-derivatives, such as 14a, might become very promising candidates to treat both cancer and AD.
RESUMEN
c-Jun N-terminal kinases (JNKs) are a family of protein kinases activated by a myriad of stimuli consequently modulating a vast range of biological processes. In human postmortem brain samples affected with Alzheimer's disease (AD), JNK overactivation has been described; however, its role in AD onset and progression is still under debate. One of the earliest affected areas in the pathology is the entorhinal cortex (EC). Noteworthy, the deterioration of the projection from EC to hippocampus (Hp) point toward the idea that the connection between EC and Hp is lost in AD. Thus, the main objective of the present work is to address if JNK3 overexpression in the EC could impact on the hippocampus, inducing cognitive deficits. Data obtained in the present work suggest that JNK3 overexpression in the EC influences the Hp leading to cognitive impairment. Moreover, proinflammatory cytokine expression and Tau immunoreactivity were increased both in the EC and in the Hp. Therefore, activation of inflammatory signaling and induction of Tau aberrant misfolding caused by JNK3 could be responsible for the observed cognitive impairment. Altogether, JNK3 overexpression in the EC may impact on the Hp inducing cognitive dysfunction and underlie the alterations observed in AD.
Asunto(s)
Enfermedad de Alzheimer , Trastornos del Conocimiento , Disfunción Cognitiva , Humanos , Corteza Entorrinal/metabolismo , Corteza Entorrinal/patología , Hipocampo/metabolismo , Enfermedad de Alzheimer/metabolismo , Trastornos del Conocimiento/metabolismo , Disfunción Cognitiva/metabolismo , Cognición , Proteínas tau/metabolismoRESUMEN
c-Jun N-terminal kinase 3 (JNK3) is suggested to play a key role in neurodegenerative disorders, especially in Alzheimer's disease (AD). However, it remains unclear whether JNK or amyloid ß (Aß) appears first in the disease onset. Postmortem brain tissues from four dementia subtypes of patients (frontotemporal dementia, Lewy body dementia, vascular dementia, and AD) were used to measure activated JNK (pJNK) and Aß levels. pJNK expression is significantly increased in AD; however, similar pJNK expression was found in other dementias. Furthermore, there was a significant correlation, co-localization, and direct interaction between pJNK expression and Aß levels in AD. Significant increased levels of pJNK were also found in Tg2576 mice, a model of AD. In this line, Aß42 intracerebroventricular injection in wild-type mice was able to induce a significant elevation of pJNK levels. JNK3 overexpression, achieved by intrahippocampal injection of an adeno-associated viral vector expressing this protein, was enough to induce cognitive deficiencies and precipitate Tau aberrant misfolding in Tg2576 mice without accelerating amyloid pathology. JNK3 overexpression may therefore be triggered by increased Aß. The latter, together with subsequent involvement of Tau pathology, may be underlying cognitive alterations in early stages of AD.